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The Genetics of Sudden Death
Wendy S. Rubenstein, MD, PhD
Northwestern University Medical School, Chicago, Ill
Reynold I. Lopez-Soler
Healthcare, Evanston, Ill
JAMA. 2001;286:1636.
Sudden cardiac death (SCD) is a widespread health problem with several known genetic etiologies. SCD generally occurs in healthy individuals who do not have other conventional cardiac risk factors. A parental history of SCD carries a high relative risk of SCD, suggesting an independent pathway with a genetic component.
William Bateson, the "father of genetics" who translated and revived Mendel's works, advised, "treasure your exceptions." Along these lines, studies of relatively rare genetic disorders of the heart can provide a guide to the numerous genetic etiologies of SCD, which may be important in the general population. For example, the synchronized ionic cascades of the cardiac action potential are manifested in disease by the ion channelopathies.1 These include congenital long QT syndrome (LQTS) which causes prolongation of the QT interval resulting in syncope, seizures or sudden death. One form of LQTS, caused by disruption of the KvLQT1 gene, is exacerbated by exercise whereas SCN5A sodium channel gene mutations are typically associated with arrhythmias at rest.2 Carriers of KvLQT1 mutations respond to  blockers and avoidance of adrenergic stimuli, while those with SCN5A mutations are exhorted to undergo placement of implantable cardioverter defibrillators since their arrhythmic events are more lethal.3 Thus, disease management can be informed by an understanding of genetic pathophysiology.
Malignant ventricular arrhythmias leading to SCD are a major final common pathway in myocardial ischemia and infarction, as well as in congestive, hypertrophic, and dilated cardiomyopathies.4 Most cases of SCD are not associated with well-characterized genetic syndromes such as LQTS. Therefore, it is often assumed that genetic mutations of SCD loci have little public health significance. However, prolongation of the QT interval during the first week of life is strongly associated with sudden infant death syndrome, perhaps caused by de novo mutations in LQTS genes.5 Moreover, drug-induced QT prolongation has been reported in patients with otherwise silent LQTS mutations.6 There could be considerable public health benefits if genetic variants for SCD were considered in the differential diagnosis for drug-induced QT prolongation, syncope, seizures, unexplained drowning, and sudden death.
It is therefore important to study allelic variation in the numerous genes involved in the rare hereditary SCD syndromes in patients with several different cardiac diseases. Subtle genetic disruptions in these genes may be responsible for more common forms of SCD. For example, several single nucleotide polymorphisms (SNPs)—changes occurring in at least 1% of the population—have been identified in genes which, when dysfunctional, cause hereditary arrhythmias and cardiomyopathies. Some of these variants may be benign, but others, either alone or in certain combinations, may lead to functional changes in the action potential, force generation, and membrane stability. It is now feasible to compare the prevalence of numerous SNPs in affected versus healthy individuals using high throughput genotyping technology. Although the genetic etiology of disease or pharmacological response may be quite complex, statistical methodologies have been developed for correlating clinical phenotype with groups of interacting genes and environmental exposures.
Genetic testing for hereditary SCD is challenging due to the need to examine multiple causative genes with numerous potential mutations, but the benefits could be great. Pinpointing the genetic cause makes subsequent intrafamilial testing highly sensitive and specific, and relatively inexpensive. SCD may be prevented in relatives of carriers by lifestyle changes and medical intervention, and noncarriers and their children can be relieved of the medical and psychological burdens of being susceptible to SCD. In addition, genetic profiles contributing to common forms of SCD may reveal more continuous degrees of risk than the all-or-nothing phenotype in LQTS but should provide a plethora of strategies for rational drug therapies and prevention.
The ultimate promise of molecular medicine is to unlock the passageways to targeted therapy. If genetic etiology plays an important role in SCD due to common heart disease, SIDS, and drug-induced QT prolongation, then genetic screening will substantially improve the medical management of these diseases. Increasing evidence of an enormous degree of allelic variation between individuals supports a prevailing theory that many different alleles collectively contribute to common diseases.7 It is now possible to begin to decipher this complexity by using the clues of classical clinical genetics and the tools of modern molecular genetics.
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7. Stephens JC, Schneider JA, Tanguay DA, et al. Haplotype variation and linkage disequilibrium in 313 human genes. Science. 2001;293:489-493.
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